Journal Article

Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor β2 promoter in breast cancer cells

Subramanyan, Smitha, Sironi, Elena, Sukumar, Saraswati, Sirchia, Silvia M, Sacchi, Nicoletta, Orlandi, Rosaria, Ferguson, Anne T

2000

Overview

Retinoic acid (RA)-resistance in breast cancer cells has been associated with irreversible loss of retinoic acid receptor β, RARβ, gene expression. Search of the causes affecting RARβ gene activity has been oriented at identifying possible differences either at the level of one of the RARβ promoters, RARβ2, or at regulatory factors. We hypothesized that loss of RARβ2 activity occurs as a result of multiple factors, including epigenetic modifications, which can pattern RARβ2 chromatin state. Using methylation-specific PCR, we found hypermethylation at RARβ2 in a significant proportion of both breast cancer cell lines and primary breast tumors. Treatment of cells with a methylated RARβ2 promoter, by means of the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (5-Aza-CdR), led to demethylation within RARβ2 and expression of RARβ indicating that DNA methylation is at least one factor, contributing to RARβ inactivity. However, identically methylated promoters can differentially respond to RA, suggesting that RARβ2 activity may be associated to different repressive chromatin states. This supposition is supported by the finding that the more stable repressive RARβ2 state in the RA-resistant MDA-MB-231 cell line can be alleviated by the HDAC inhibitor, trichostatin A (TSA), with restoration of RA-induced RARβ transcription. Thus, chromatin-remodeling drugs might provide a strategy to restore RARβ activity, and help to overcome the hurdle of RA-resistance in breast cancer.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: Biological and medical sciences / Breast cancer / Cell physiology / Cell receptors / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Chromatin / Chromatin remodeling / Demethylation / DNA methylation / DNA methyltransferase / Drug therapy / Epigenetics / Fundamental and applied biological sciences. Psychology / Gene expression / Genetic aspects / Histone deacetylase / Molecular and cellular biology / Physiological aspects / Promoters / Promoters (Genetics) / Transcription / Trichostatin A / Tumor cell lines